Th17 cells, which secrete interleukin 17 (IL-17) and IL-22 comprise a recently identified subset of CD4+ T cells distinct from the Th1 and Th2 subsets. More and more evidence indicates that Th17 cells are involved in the pathogenesis of various autoimmune/inflammatory diseases. Thus, a more complete understanding of the molecular mechanisms involved in the regulation of Th17 immune responses would provide insights into the pathogenesis and treatment of chronic inflammatory diseases. Although RORgt is necessary and sufficient for the generation of Th17 cells, the molecular mechanisms underlying the phenotypic and functional diversity of Th17 cells are not fully understood. We now find that interferon regulatory factor (IRF) 8, a transcription factor of the IRF family, plays a critical role in the control of Th17 cell differentiation. IRF8-deficiency in both conventional and T cell specific conditional knock out mice leads to more robust Th17 cell differentiation without effects on either Th1 or Th2 cell lineages. Furthermore, transfer of IRF8-/- CD4+CD45Rbhi cells into RAG-/- mice induces more severe colitis compared to control CD4+CD45Rbhi cells. In addition, mice reconstituted with IRF8-/- cells had a significantly higher percentage of IL-17-producing cells than control mice. The results suggest that IRF8 negatively regulates the development of Th17 immune response resulting in the control of inflammation. Furthermore, we have demonstrated that IRF8 physically interacts with RORgt resulting in the suppression of IL-17 transcription. These findings define a novel transcriptional inhibitor of Th17 cell differentiation and highlight the importance of intrinsic genetic programs directing the silence for Th17 immune response. Since Th17 immune response is important for human inflammatory diseases, it is critical to define the function of IRF8 in Th17, Th1, and Th2 cell differentiation, to elucidate in detail how IRF8 is regulated in T cells, and to characterize expression of IRF8 in the different cell compartments (macrophages, dendritic cells and T cells) in the development of colitis.